Pneumocystis carinii pneumonia (PCP) is the leading killer of patients with AIDS. Similarly, Toxomplasma gondii, a pervasive parasitic protozoan, causes significant morbidity and mortality among AIDS patients. Current treatment regimens for both P. carinii and T. gondii infections often produce severe side effects, leading to the cessation of therapy. It is widely recognized that new drugs having novel mechanisms of action are urgently needed for the treatment of PCP and toxoplasmosis. We have initiated two structure-based drug design programs to make improved inhibitors and toxic substrates of T. gondii hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and uracil phosphoribosyltransferase (UPRT), T. gondii dihydrofolate reductase-thymidylate synthase (DHFR-TS) and P. carinii DHFR.